Acne vulgaris is a skin condition that affects over 85% of all people. Acne is a term for a medical condition of plugged pores typically occurring on the face, neck, and upper torso. Following are four primary factors that lead to the formation of acne vulgaris; (1) increased sebum output resulting in oily, greasy skin; (2) increased bacterial activity normally due to an overabundance of Propionibacterium acnes bacteria; (3) plugging (hypercornification) of the follicle or pilosebaceous duct; and (4) production of inflammation by substances leaking into the dermis which cause inflammatory reactions. The plugged pores result in blackheads, whiteheads, pimples or deeper lumps such as cysts or nodules. Severe cases of acne can result in permanent scarring or disfiguring.
Acne occurs when the oil glands of the skin called sebaceous glands produce an increased amount of oil. The sebaceous glands are connected to canals in the skin called hair follicles that terminate in openings in the skin called pores. The increased amount of oil secreted by the sebaceous glands is caused by an increase in androgen hormones in both males and females during adolescence or puberty. Accompanying the increase in the amount of oil secreted by the sebaceous glands is an increase in the shedding of the skin lining the hair follicles. The increase in the amount of secreted oil in combination with the increase in the shedding of the skin lining the hair follicles increases the likelihood of the pores being clogged by the shedding skin. A pore clogged by the shedding skin is referred to as a comedo.
The Propionibacterium acnes (P. acnes) normally reside on the skin. The propionibacterium acnes invade the clogged follicles and grow in the mixture of oil and cells in the hair follicle. It produces chemicals that stimulate inflammation resulting in acne. Acne lesions range in severity from blackheads, whiteheads and pimples to more serious lesions such as deeper lumps, cysts and nodules.
In many instances, the inflammation within the acne lesion provides an opportunity for secondary infections to invade and grow in the inflamed hair follicle. Some of these secondary infections can be more serious and more resistant to treatment than the primary Propionibacterium acnes infection.
Various products and methods are currently available for treatment of acne. The only products that have anti-sebum activity are estrogens and 13 cis-retinoic acid (isotretinoin) and these must be used systemically to be effective. Isotretinoin is used to treat only severe cystic or conglobate acne (Anja Thielitz et al., JDDG, 6, 2008, Pp: 1023-1031). Because of its teratogenic properties, birth defects can occur. Isotretinoin is a powerful drug and can elevate triglycerides, total cholesterol and decrease high-density lipoproteins (HDL). Other side effects include dry skin, dry eyes, itching, headaches, nosebleed, and photosensitivity. It is generally taken for 4-5 months to see improvement. However, all topical retinoic acid preparations may be irritating, and this may contribute to underutilization in clinical practices (Cynthia E Irby et al., J. of Adolescent Health, 43, 2008, Pp-421-424). Recently, one brand of oral contraceptive has been approved for the treatment of acne for patients who request birth control.
A number of topical and systemic agents are used to lower the number of bacteria that colonize the follicular duct. These include benzoyl peroxide (BP), and BP (5%), erythromycin (3%) combination (Benzamycin®). BP has antibacterial activity and drying effects and is available over the counter or by prescription. BP is applied once or twice daily for 1-2 months. BP can produce erythema and peeling of skin. BP is often tried first for both non-inflammatory and mild inflammatory acne. Other topical antibiotics include clindamycin and erythromycin. It is known that the combination of topical antibiotic such as clindamycin with other topical agents is more therapeutically effective than either drug used alone (James Q. Del Rosso et al., Drug therapy Topics, Volume 85; January 2010, Pp: 15-24). These topical antibiotics are used as solutions, lotions or gels by prescription only. Usually they are applied once or twice daily and results are seen in 1-2 months. Another topical agent, azelaic acid 20% (Azelex®) also has mild antibacterial effects.
Systemic antibiotics include tetracycline and its analogs, which are used in low doses for years or until the end of the acne prone years. Most patients with mild inflammatory acne receive a combination of topical antibiotics and tretinoin or other retinoid. Bacterial resistance does occur so antibiotics may be changed or BP is substituted since resistance does not occur with BP. More severe acne requires systemic antibiotics and topical retinoid. The most severe must receive oral isotretinoin for 4-5 months.
Various topical products containing clindamycin phosphate, adapalene or their combination are currently available in market. For example, Clindac® 1% clindamycin gel [marketed by Galderma], Adaferrin® 0.1% adapalene gel [marketed by Galderma], Deriva® MS 0.1% micropshere adapalene gel [marketed by Glenmark Pharmaceuticals Ltd.], Achilles®-C 0.1% adapalene and 1% clindamycin gel [marketed by Sandoz Ltd.].
There are no drugs that directly affect the inflammatory acne. The retinoids do have some anti-inflammatory properties, but these are poorly described. Topical steroid and even systemic steroids have been used to abort a severe flare of fulminant acne, but these are limited uses because of the side effects. Benzoyl peroxide gels are sometimes used as first aid on acne lesions. These function as a “drawing poultice”, but data supporting this use is not available.
The treatment for acne centers around opening the pore, killing P. acnes, reducing sebum production and regulating inflammatory responses. Retinoids are the agents to reduce sebum production and open the pore. As a topical agent, adapalene (Differin®) or tretinoin (Retin-A®) is used for mild and moderate acne.
It is often advantageous to be able to deliver the drug over a period of time, such that a desired level of the drug in the target tissue is achieved for a period of time sufficient to achieve the desired result, e.g., killing most of a population of infectious bacterial. Dermatological conditions, such as acne, require multiple delivery strategies because they have multiple delivery requirements, such as killing skin surface bacteria while also penetrating deep into inflamed sebaceous glands to kill bacteria in that locus.
U.S. Patent Publication No. 2010/0015216 discloses composition for the treatment of acne comprising: a first therapeutic agent selected from the group consisting of salicylic acid, azelaic acid, adapalene, benzoyl peroxide, antibiotics and combinations thereof; and a second therapeutic agent which comprises a taurine species.
U.S. Pat. No. 5,962,571 discloses a pharmaceutical composition for the treatment of acne having an acne reduction component in an amount sufficient to reduce the redness and blemishes associated with acne.
U.S. Patent Publication No. 2010/0029781 discloses a method of preparing a solvent-microparticle (SMP) topical gel formulation comprising a bioactive drug wherein the formulation comprises the drug dissolved in a liquid and the drug in a microparticulate solid form dispersed in the liquid.
U.S. Patent Publication No. 2010/0068284 discloses a stable fixed dose topical formulation comprising therapeutically effective amounts of adapalene-containing microparticles and clindamycin. However, such formulation may not significantly reduce the incident and severity of acne lesions.
U.S. Pat. No. 5,894,019 discloses topical compositions comprising lipid and essentially free of emulsifiers and surfactants.
European Patent No. EP 0671903 B discloses topical compositions in the form of submicron oil spheres.
Most of the topical preparations contain vehicles comprising permeation enhancers, solvents, and high amount of surfactants to achieve topical compositions for acne treatment. But use of these agents is harmful, especially in chronic application, as many of them cause undesirable effects such as irritation and dryness and resulting in poor patient tolerability.
In general, current products are effective in reducing the clinical observation of acne but it does not completely eliminate the condition, hence the consumer is not completely satisfied with results of these products.
Although various over-the-counter products are commercially available to counteract acne condition, such as anti-acne agents for topical use, including salicylic acid, sulfur, lactic acid, glycolic acid, pyruvic acid, urea, resorcinol, N-acetylcysteine, retinoic acid, isotretinoin, tretinoin, adapalene, tazoretene, antibacterials such as clindamycin and erythromycin, vitamins such as zinc, folic acid and nicotinamide, benzoyl peroxide, octopirox, triclosan, azelaic acid, phenoxyethanol, phenoxypropanol, and flavinoids, however, these agents tend to lack in potential to mitigate the acne condition and may have negative side effects when devised in conventional topical formulations.
Therefore, despite of the wide availability of products for acne, there exists a need to improve effectiveness of anti-acne pharmaceutical agents by developing suitable topical preparations which facilitate drug permeation through the skin, and resulting in enhanced therapeutic activity alongside reducing the instance and severity of adverse events resulting from topical use of these agents.